Apoptosis is a normal physiologic process that determines individual cell death and ultimate deletion of the cell from tissue. For review see, Apoptosis the Molecular Basis of Cell Death, Tomei and Cope, eds., Current Communications in Cell and Molecular Biology 3, Cold Spring Harbor Laboratory Press, New York, 1991. Apoptosis is a process of programmed cell death involved in a variety of normal and pathogenic biological events and can be induced by a number of unrelated stimuli. Changes in the biological regulation of apoptosis also occur during aging and are responsible for many of the conditions and diseases related to aging.
Recent studies of apoptosis have implied that a common metabolic pathway leading to cell death may be initiated by a wide variety of signals, including changes in hormone levels, serum growth factor deprivation, chemotherapeutic agents and ionizing radiation. Wyllie (1980) Nature, 284:555-556; Kanter et al. (1984) Biochem. Biophys. Res. Commun., 155:324-331; and Kruman et al. (1991) J. Cell. Physiol., 148:267-273. Agents that affect the biological control of apoptosis thus have therapeutic utility in a wide variety of conditions.
Fas, also known as APO-1, is a cell surface protein belonging to the tumor necrosis factor/nerve growth factor receptor family, each of whose members have been shown to be capable of mediating apoptosis. The cloning of Fas is described in PCT publication No. WO 91/10448; and European Patent Application Publication Number 0510691. Fas is a transmembrane (TM) protein of 34,971 deduced molecular weight and an apparent molecular weight of about 45,000 which may be due to glycosylation. The mature Fas molecule consists of 319 amino acid residues of which 157 are extracellular, 17 constitute the TM domain and 145 are intracellular. A variety of cell types express Fas on their surface. Interestingly, Fas expression is increased in activated T-cells including CD4.sup.+ and CD8.sup.+ cells.
Certain antibodies specific for Fas have been shown to induce death of cells that express Fas on their surfaces, by an apoptotic mechanism. Early studies indicated that therapeutic uses of antibodies specific to Fas would be effective in treating a variety of diseases, Itoh et al. (1991) Cell, 66:233-243; Krammer et al. (1991) in Apoptosis: The Molecular Basis Of cell Death, (Tomei and Cope, eds.), Cold Spring Harbor Laboratory Press, New York; Oehm et al. (1992) J. Biol. Chem., 267:10709-10715; and Rouvier et al. (1993) J. Exp. Med., 177:195-200. It has now been found that administration of anti-Fas antibodies can be lethal. Ogasawara et al. (1993) Nature 364:806-809. It has also been found that purified Fas blocks the cytocidal effects of anti-Fas. Oehm et al. (1992).
Increased levels of T cell surface Fas have also been associated with tumor cells and HIV-infected cells. HIV-infected cells are more sensitive to anti-Fas antibodies, yet the significance of the association of Fas with HIV infection has not yet been determined.
The endogenous Fas ligand, responsible for recognizing Fas and inducing apoptosis, has not been identified, although some AIDS patients have been shown to have increased levels of anti-Fas autoantibodies. Oehm et al. (1991). Moreover, T cell mediated cytotoxicity has been shown to be involved in Fas-mediated apoptosis.
All references cited herein both infra and supra are hereby incorporated herein by reference.